Oxidative Impairment of Mitochondrial Electron Transport Chain Complexes in Rostral Ventrolateral Medulla Contributes to Neurogenic Hypertension

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Abstract
The role for mitochondrial electron transport chain (ETC) in neurogenic hypertension is unidentified. We evaluated the hypothesis that feedforward depression of mitochondrial ETC functions by superoxide anion (O 2 ·− ) and hydrogen peroxide (H 2 O 2 ) in rostral ventrolateral medulla (RVLM), a brain stem site that maintains sympathetic vasomotor tone and contributes to oxidative stress and neural mechanism of hypertension. Compared with normotensive Wistar-Kyoto rats, spontaneously hypertensive rats exhibited mitochondrial ETC dysfunctions in RVLM in the forms of depressed complex I or III activity and reduced electron coupling capacity between complexes I and III or II and III. Microinjection of coenzyme Q 10 into RVLM of spontaneously hypertensive rats reversed the depressed ETC activity and augmented O 2 ·− production and hypertensive phenotypes. This mobile electron carrier also antagonized the elevated H 2 O 2 in RVLM and vasopressor responses to complex I (rotenone) or III (antimycin A) inhibitor in Wistar-Kyoto or prehypertensive rats. Intracerebroventricular infusion of angiotensin II promoted mitochondrial ETC dysfunctions in Wistar-Kyoto rats, and coenzyme Q 10 or gene knockdown of the p22 phox subunit of NADPH oxidase antagonized the resultant elevation of H 2 O 2 in RVLM. Overexpression of superoxide dismutase or catalase in RVLM of spontaneously hypertensive rats by gene transfer reversed mitochondrial dysfunctions and blunted the augmented O 2 ·− and H 2 O 2 in RVLM. We conclude that O 2 ·− - and H 2 O 2 -dependent feedforward impairment of mitochondrial ETC complexes because of predisposed downregulation of superoxide dismutase or catalase and a cross-talk between NADPH oxidase-derived O 2 ·− and ETC enzymes contribute to chronic oxidative stress in the RVLM of spontaneously hypertensive rats, leading to augmented sympathetic vasomotor tone and hypertension.

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